This proposal addresses two challenges of great importance to child health: defining genetic etiologies of autism spectrum disorders (ASD) and establishing clinical-pathophysiological mechanisms in ASD. Autism is common in the US, affecting ~1% of the population, and is heterogeneous with regard to etiology, pathogenesis, and clinical presentation. A known, genetic risk factor for ASD is the male sex chromosome disorder, 47,XYY syndrome (XYY). Approximately one third of males with XYY satisfy diagnostic criteria for ASD, and XYY is significantly overrepresented in autism cohorts; yet this significant association is understudied. Coupled with the 4:1 male predominance for ASD, the increased risk for ASD in XYY suggests the involvement of sex-linked genes (i.e. increased Y chromosome gene copy number in XYY leads to over- expression of Y-linked genes related to brain development and function, thereby increasing ASD risk). The overarching goals of this proposal are to 1) better understand the particular role of the Y-chromosome in ASD, given the male preponderance and likely involvement of sex-linked genes, 2) to improve understanding of the neuroanatomic and neurophysiologic correlates of ASD in this relatively genetically homogeneous model of autism 3) to enlighten our understanding of convergent pathophysiological mechanisms that may generalize to the broader autism spectrum, and 4) to characterize the neural correlates of behavioral symptoms in boys with XYY, leading towards future targeted treatments and interventions. To accomplish these goals, we will contrast the clinical, behavioral and neurophysiological markers of ASD in four groups (20 per group) of age-matched (6-16 yrs) boys: XYY with ASD (XYY+ASD), XYY without ASD (XYY-ASD), ASD-Idiopathic (ASD-I) and typically developing (TD) controls. An existing well-characterized dataset will be used for ASD-I and TD cohorts. Cognitive and behavioral phenotypes will be obtained from 80 boys with XYY to yield 40 (20 XYY+ASD / 20 XYY-ASD) subjects suitable for imaging. Aims 1 and 2 seek to establish commonalities between the XYY+ASD and ASD-I populations as well as specificities of the ASD phenotype within the XYY population (XYY+ASD vs XYY-ASD) by comparing clinical/behavioral markers of ASD (in Aim 1) and local cortical neurophysiologic (magnetoencephalography) markers (in Aim 2) in the four groups. The mechanisms underlying the neurophysiologic measures will be probed in Aim 3, via the neuro- chemical magnetic resonance spectroscopy of key neurotransmitters GABA and glutamate and quantitative diffusion MRI. Aim 4 examines interactions between clinical/behavioral phenotypic markers and neurophys- iological, neurochemical and neuroimaging measures and will demonstrate that ASD in XYY+ASD shares a neurobiological basis with ASD-I. This innovative study takes advantage of the methodical ASD characteriza- tion of the unique XYY cohort (Dr. Ross), extensive ASD-I neuroimaging expertise (Dr. Roberts), compelling synergies of the multidisciplinary team, multi-modal data collection, and sophisticated multivariate analysis.